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Telomere length is greater in ALS than in controls: a whole genome sequencing study

Telomere length is greater in ALS than in controls: a whole genome sequencing study
Telomere length is greater in ALS than in controls: a whole genome sequencing study

BACKGROUND: Amyotrophic lateral sclerosis is a neurodegenerative disease of motor neurons resulting in progressive paralysis and death, typically within 3-5 years. Although the heritability of ALS is about 60%, only about 11% is explained by common gene variants, suggesting that other forms of genetic variation are important. Telomeres maintain DNA integrity during cellular replication and shorten naturally with age. Gender and age are risk factors for ALS and also associated with telomere length. We therefore investigated telomere length in ALS.

METHODS: We estimated telomere length by applying a bioinformatics analysis to whole genome sequence data of leukocyte-derived DNA from people with ALS and age and gender-matched matched controls in a UK population. We tested the association of telomere length with ALS and ALS survival.

RESULTS: There were 1241 people with ALS and 335 controls. The median age for ALS was 62.5 years and for controls, 60.1 years, with a male-female ratio of 62:38. Accounting for age and sex, there was a 9% increase of telomere length in ALS compared to matched controls. Those with longer telomeres had a 16% increase in median survival. Of nine SNPs associated with telomere length, two were also associated with ALS: rs8105767 near the ZNF208 gene (p = 1.29 × 10-4) and rs6772228 (p = 0.001), which is in an intron for the PXK gene.

CONCLUSIONS: Longer telomeres in leukocyte-derived DNA are associated with ALS, and with increased survival in those with ALS.

2167-8421
1-6
Al Khleifat, Ahmad
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Iacoangeli, Alfredo
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Shatunov, Aleksey
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Fang, Ton
b25b4763-846f-4513-9391-c57deb7ca6e0
Sproviero, William
f0231df6-ec34-456b-976d-d66ec3f3228f
Jones, Ashley R.
4014edfb-94f8-4c42-aaf7-0a437e0182bf
Opie-Martin, Sarah
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Morrison, Karen E.
f00890f0-2fde-4dbd-a73b-7422e1b0ede8
Shaw, Pamela J.
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Shaw, Christopher E.
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Powell, John F.
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Dobson, Richard
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Newhouse, Steven J.
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Al-Chalabi, Ammar
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Al Khleifat, Ahmad
36f3f499-11a5-4b0a-a617-23d44eab04e9
Iacoangeli, Alfredo
50f630e7-cf3a-4040-9294-ab567fce82d7
Shatunov, Aleksey
e4422e0f-4878-404a-8e9e-fc45b4d5d9bd
Fang, Ton
b25b4763-846f-4513-9391-c57deb7ca6e0
Sproviero, William
f0231df6-ec34-456b-976d-d66ec3f3228f
Jones, Ashley R.
4014edfb-94f8-4c42-aaf7-0a437e0182bf
Opie-Martin, Sarah
9030499e-3b21-45f6-bd50-43fdcc3d3059
Morrison, Karen E.
f00890f0-2fde-4dbd-a73b-7422e1b0ede8
Shaw, Pamela J.
3d0a5c6f-9610-45be-a0bc-5b6888003028
Shaw, Christopher E.
ad432fe6-4928-445b-a3e1-aaba83c6a530
Powell, John F.
3bd035d2-40a4-457c-a64d-0674173cfb7b
Dobson, Richard
c54b8306-dfbc-4e20-8005-3ee347c1fb3d
Newhouse, Steven J.
01d98226-a9e4-4de1-a3f5-ea4edf6235ab
Al-Chalabi, Ammar
8ac40bc3-a3c0-47ad-afa7-37e08f7aab6f

Al Khleifat, Ahmad, Iacoangeli, Alfredo, Shatunov, Aleksey, Fang, Ton, Sproviero, William, Jones, Ashley R., Opie-Martin, Sarah, Morrison, Karen E., Shaw, Pamela J., Shaw, Christopher E., Powell, John F., Dobson, Richard, Newhouse, Steven J. and Al-Chalabi, Ammar (2019) Telomere length is greater in ALS than in controls: a whole genome sequencing study. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 1-6. (doi:10.1080/21678421.2019.1586951).

Record type: Article

Abstract

BACKGROUND: Amyotrophic lateral sclerosis is a neurodegenerative disease of motor neurons resulting in progressive paralysis and death, typically within 3-5 years. Although the heritability of ALS is about 60%, only about 11% is explained by common gene variants, suggesting that other forms of genetic variation are important. Telomeres maintain DNA integrity during cellular replication and shorten naturally with age. Gender and age are risk factors for ALS and also associated with telomere length. We therefore investigated telomere length in ALS.

METHODS: We estimated telomere length by applying a bioinformatics analysis to whole genome sequence data of leukocyte-derived DNA from people with ALS and age and gender-matched matched controls in a UK population. We tested the association of telomere length with ALS and ALS survival.

RESULTS: There were 1241 people with ALS and 335 controls. The median age for ALS was 62.5 years and for controls, 60.1 years, with a male-female ratio of 62:38. Accounting for age and sex, there was a 9% increase of telomere length in ALS compared to matched controls. Those with longer telomeres had a 16% increase in median survival. Of nine SNPs associated with telomere length, two were also associated with ALS: rs8105767 near the ZNF208 gene (p = 1.29 × 10-4) and rs6772228 (p = 0.001), which is in an intron for the PXK gene.

CONCLUSIONS: Longer telomeres in leukocyte-derived DNA are associated with ALS, and with increased survival in those with ALS.

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Accepted/In Press date: 10 February 2019
e-pub ahead of print date: 1 April 2019

Identifiers

Local EPrints ID: 430197
URI: https://eprints.soton.ac.uk/id/eprint/430197
ISSN: 2167-8421
PURE UUID: cac709f9-31d3-43e5-ab96-710b4557dce5
ORCID for Karen E. Morrison: ORCID iD orcid.org/0000-0003-0216-5717

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Date deposited: 16 Apr 2019 16:30
Last modified: 17 Aug 2019 00:30

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Contributors

Author: Ahmad Al Khleifat
Author: Alfredo Iacoangeli
Author: Aleksey Shatunov
Author: Ton Fang
Author: William Sproviero
Author: Ashley R. Jones
Author: Sarah Opie-Martin
Author: Pamela J. Shaw
Author: Christopher E. Shaw
Author: John F. Powell
Author: Richard Dobson
Author: Steven J. Newhouse
Author: Ammar Al-Chalabi

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